Rh-Catalyzed Enantioselective Hydrogenation of Di- and Tri-Substituted Enamides Enabled by Easily Tunable P-Stereogenic <i>N</i>-Phosphinyl Phosphoramidite Ligands

Abstract

A modular mixed donor P-stereogenic narrow bite angle N -phosphinyl phosphoramidite ligand library ( JoSoPhos ) was synthesized. The JoSoPhos ligand library was applied to the asymmetric synthesis of the anti-Parkinson therapeutic Rasagiline in >99% ee and 79% yield via the Rh-catalyzed asymmetric hydrogenation of 1-indanone derived enamide as the key step. The Rh/ JoSoPhos catalyst also demonstrated high catalytic performance in the asymmetric hydrogenation of vinyl enamides with a broad functional group tolerance up to >99% ee. Other challenging trisubstituted vinylic olefins were also reduced with excellent enantioselection. A range of trisubstituted carbocyclic olefins bearing different functional groups were also reduced delivering products with >99% ee’s. Pharmaceutically important chiral primary amines have also been prepared using the hydrogenation/hydrolysis method in close to enantiopure form. Isotope labeling studies showed the Rh/ JoSoPhos catalyzed enantioselective hydrogenation of di- and trisubstituted enamide is an isomerization-free direct asymmetric hydrogenation process.